Orexins (hypocretins) directly interact with neuropeptide YPOMC and glucose-responsive neurons to regulate Ca2+ signaling in a reciprocal manner to leptin:: orexigenic neuronal pathways in the mediobasal hypothalamus
Orexins (hypocretins) directly interact with neuropeptide YPOMC and glucose-responsive neurons to regulate Ca2+ signaling in a reciprocal manner to leptin:: orexigenic neuronal pathways in the mediobasal hypothalamus
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DOI：
10.1111/j.1460-9568.2004.03255.x
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发表时间：
2004-03-01
影响因子：
3.4
通讯作者：
Yada, T
中科院分区：
文献类型：
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作者：
Muroya, S;Funahashi, H;Yada, T
食欲素- a和-B（下丘脑分泌素-1和-2）与刺激进食有关。在这里，我们展示了食欲素在大鼠体内的致氧作用的效应神经元和信号机制。免疫组织化学方法显示，食欲素轴突末端与大鼠弓形核（ARC）内神经肽Y （NPY）和促黑色素皮质素（POMC）阳性神经元接触。在ARC中微量注射食欲素显著增加了食物摄入量。在ARC中分离的神经元中，Orexins增加了胞质Ca2+浓度（[Ca2+](i)），随后被证明对NPY具有免疫反应性。[Ca2+](i)的增加被磷脂酶C （PLC）、蛋白激酶C （PKC）和Ca2+摄取到内质网的阻滞剂抑制。与食欲素- b相比，食欲素- a对食物摄入的刺激和NPY神经元中[Ca2+](i)的增加更大，表明食欲素-1受体（OX1R）的参与。相比之下，orexin-A和-B在含有pomc的神经元中等效地减弱[Ca2+](i)振荡并降低[Ca2+](i)水平。这些作用被百日咳毒素抵消，这表明食欲素-2受体和gtp结合蛋白的Gi/Go亚型参与其中。食欲素还降低了腹内侧下丘脑（VMH）中葡萄糖反应神经元中的[Ca2+](i)水平，这是一个饱腹感中心。瘦素对这三类神经元产生相反的作用。这些结果表明，食欲素以与瘦素相反的方式直接调节ARC和VMH中的NPY POMC和葡萄糖反应神经元。Orexin-A通过OX1R-PLC-PKC和IP3途径在NPY神经元中唤起Ca2+信号。这些神经通路和细胞内信号机制可能在食欲素的促氧作用中起关键作用。
Orexin-A and -B (hypocretin-1 and -2) have been implicated in the stimulation of feeding. Here we show the effector neurons and signaling mechanisms for the orexigenic action of orexins in rats. Immunohistochemical methods showed that orexin axon terminals contact with neuropeptide Y (NPY)- and proopiomelanocortin (POMC)-positive neurons in the arcuate nucleus (ARC) of the rats. Microinjection of orexins into the ARC markedly increased food intake. Orexins increased cytosolic Ca2+ concentration ([Ca2+](i)) in the isolated neurons from the ARC, which were subsequently shown to be immunoreactive for NPY. The increases in [Ca2+](i) were inhibited by blockers of phospholipase C (PLC), protein kinase C (PKC) and Ca2+ uptake into endoplasmic reticulum. The stimulation of food intake and increases in [Ca2+](i) in NPY neurons were greater with orexin-A than with orexin-B, indicative of involvement of the orexin-1 receptor (OX1R). In contrast, orexin-A and -B equipotently attenuated [Ca2+](i) oscillations and decreased [Ca2+](i) levels in POMC-containing neurons. These effects were counteracted by pertussis toxin, suggesting involvement of the orexin-2 receptor and Gi/Go subtypes of GTP-binding proteins. Orexins also decreased [Ca2+](i) levels in glucose-responsive neurons in the ventromedial hypothalamus (VMH), a satiety center. Leptin exerted opposite effects on these three classes of neurons. These results demonstrate that orexins directly regulate NPY POMC and glucose-responsive neurons in the ARC and VMH, in a manner reciprocal to leptin. Orexin-A evokes Ca2+ signaling in NPY neurons via OX1R-PLC-PKC and IP3 pathways. These neural pathways and intracellular signaling mechanisms may play key roles in the orexigenic action of orexins.